This invention relates to 1-substituted-aminoalkoxyphenyl-2-methylene-1-alkanones and a method of preparing the same, of the following general formula: ##STR1## wherein R is a straight or branched chain lower alkyl radical of from 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, etc. or trihalomethyl substituted lower alkyl (C.sub.1-5) radical such as 2,2,2-trifluoroethyl, 2,2,2-trifluoroisopropyl, or a cycloalkyl radical of 3 to 6 carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, etc. or the radicals ##STR2## in which X.sup.1 is hydrogen, halogen or lower alkyl having from 1-5 carbon atoms and m is an integer from 1 to 5; X represents similar or dissimilar members selected from the group consisting of hydrogen, straight or branched chain lower alkyl having from 1-5 carbon atoms or halogen such as chlorine, bromine, iodine or fluorine, or when taken together two X radicals on adjacent carbon atoms of the benzene ring to which they are attached they may be joined to form the 1,3-butadienylene linkage, i.e. --CH.dbd.CH--CH.dbd.CH--; n is an integer from 1 to 4; and R.sup.1 is alkylaminoalkyl, such as dimethylaminoethyl, diethylaminoethyl, diethylaminopropyl, dimethylaminoisobutyl, etc. N-alkyl substituted five-membered saturated heterocycles containing one N atom, such as pyrrolidino-N-ethyl, N-alkyl substituted six-membered saturated heterocycles containing one N atom, such as piperidinoethyl or N-alkyl substituted six-membered saturated heterocycles containing one O and one N atoms, such as morpholinoethyl, a nitrogen containing heterocyclic-alkyl group, such as pyridylmethyl, pyridylethyl and the like and their pharmaceutically acceptable acid addition salts, such as their hydrochlorides, isethionates, sulfates, acetates, propionates, maleates, succinates, benzenesulfonates, p-toluenesulfonates, and the like.
The products of this invention are antiallergic agents which can be used in the treatment of conditions associated with allergies, such as asthma, asthmatic form bronchitis of allergic origin. When administered in therapeutic dosages, in conventional vehicles, the instant products effectively alleviate conditions usually associated with allergies, particularly those associated with histamine.
The preferred embodiment of the invention, i.e., those compounds which possess the greatest antiallergic activity, are those which have the following general formula: ##STR3## wherein R.sup.2 is straight or branched chain lower alkyl, X.sup.2 is hydrogen, halogen or methyl, X.sup.3 is halogen or methyl and R.sup.3 is lower alkylamino lower alkyl, morpholino lower alkyl or pyridylmethyl.
One of the methods of preparing the instant compounds involves a two step process. In the first, the 4-alkanoylphenols are etherified with a substituted aminoalkyl halide or pyridylmethyl halide such as the chloride, bromide, or iodide, viz: ##STR4##
In the second stage the ethers Ia thus formed are converted to the salts of a Mannich base Ib by reacting them with a salt of a secondary amine in the presence of formaldehyde or paraformaldehyde and then treating the Mannich salt with a weak base to deaminate the same and form the final product, II, viz: ##STR5##
The first stage or etherification is generally carried out by adding a solution of the substituted aminoalkyl halide, preferably the chloride in a solvent such as isopropanol to an equimolar solution of the 4-alkanoylphenol in the same solvent containing an alkali hydroxide such as KOH, NaOH, etc. and heating to complete the reaction. Then the reaction mixture is cooled, filtered and concentrated to dryness. The residue is extracted with a solvent such as ether and the solvent evaporated or distilled to recover the residual etherified product Ia.
These 1-(substituted aminoalkoxyphenyl)-1-alkanones having the general formula: ##STR6## wherein R, R.sup.1, X and m are as defined hereinbefore, are in themselves new products useful as intermediates in the preparation of the final products II, namely 1-(substituted-aminoalkoxyphenyl)-2-methylene-1-alkanones.
In the second stage, the aforementioned intermediates Ia are converted to the salts of a Mannich base as indicated above, using dimethyl amine as the preferred secondary amine. Weak bases other than sodium bicarbonate can of course also be used to effect dehydroamination of the Mannich salts. Generally a mixture of the ether Ia, the dimethylamine hydrochloride and the formaldehyde or paraformaldehyde in a molar ratio of 1:1:2 plus conc. HCl are heated on a steam bath for a few hours. The mixture is digested with water and filtered and to the filtrate containing the Mannich salt is added an aqueous solution of sodium bicarbonate and again heated on a steam bath, after which the reaction product is extracted with a solvent, such as ether, washed, dried and distilled in vacuo to obtain the final product II, namely 1-(substituted-aminoalkoxyphenyl)-2-methylene-1-alkanones.
A second synthetic method involves the reaction of a (2-methylenealkanoyl)phenol III with a substituted-aminoalkyl halide, such as chloride, bromide or iodide, in the presence of a base. Thus, ##STR7##
This reaction is carried out by adding to a solution of the (2-methylenealkanoyl)phenol III in an inert solvent such as dimethylformamide, N-methylpyrrolidinone and the like, a base such as potassium carbonate, sodium carbonate and the like. The reaction mixture is then treated with a substituted aminoalkyl halide and the mixture heated at 30.degree.-70.degree. for 1 to 6 hours. The product is isolated by adding water to the reaction mixture, extracting the product with ether, drying over an anhydrous sodium sulfate and distilling at reduced pressure.
The free bases prepared by either method can be converted to the desired acid addition salts by dissolving the base in a solvent such as ether, benzene, carbon tetrachloride and the like and adding an equivalent weight of the appropriate acid, such as hydrochloric acid, isethionic acid, sulfuric acid, acetic acid, propionic acid, maleic acid, malic acid, succinic acid, benzene sulfonic acid, p-toluenesulfonic acid, filtering the acid addition salt and drying.